Vaccines Flashcards
explain vaccine efficacy and vaccine effectiveness
Vaccine Efficacy:
Definition: Vaccine efficacy is a measure of the effectiveness of a vaccine in controlled, ideal conditions such as clinical trials or laboratory settings.
Setting: It is determined during the rigorous and controlled environment of clinical trials, where researchers closely monitor and control the conditions under which the vaccine is administered and its outcomes are observed.
Calculation: It is calculated using the relative risk reduction formula and is expressed as a percentage. The formula is (Attack rate in the unvaccinated group - Attack rate in the vaccinated group) / Attack rate in the unvaccinated group.
Limitation: Efficacy may sometimes differ from real-world effectiveness due to factors like variations in the population, natural exposure, and other conditions not replicated in clinical trials.
Vaccine Effectiveness:
Definition: Vaccine effectiveness is a measure of how well a vaccine performs in the real world, in routine conditions, and within a specific population.
Setting: It is assessed post-licensure, after the vaccine is widely distributed and used in the general population. It considers factors like the characteristics of the circulating strains, the target population’s health status, and other variables.
Calculation: It is usually calculated by comparing the incidence of the disease in vaccinated and unvaccinated individuals in a real-world setting.
Real-world Factors: Vaccine effectiveness may be influenced by factors such as vaccine coverage, the level of natural exposure to the pathogen, and the emergence of new variants.
explain the clinical development phases of a vaccine, along with important ethical considerations
Ethical Principles - Informed Consent:
Explanation: Before any clinical trials involving human subjects, obtaining informed consent is crucial. This involves providing potential participants with detailed information about the study, including its purpose, potential risks and benefits, procedures involved, and their rights. Participants must voluntarily agree to participate after understanding this information.
Phase I Clinical Trials:
Objective: Phase I trials are the first step in testing a new vaccine in humans.
Scale: These trials typically involve a small number of healthy volunteers.
Focus: The primary goal is to assess the vaccine’s safety in humans and to determine the type of immune response it elicits.
Phase II Clinical Trials:
Objective: Phase II trials aim to further assess the safety and efficacy of the vaccine.
Scale: They involve a larger number of participants, often including individuals who represent the target population.
Focus: Researchers evaluate the vaccine’s ability to produce the desired immune response, its efficacy against artificial infection, and its performance in preventing clinical disease. Safety and side effects are closely monitored.
Phase III Clinical Trials:
Objective: Phase III trials involve a much larger number of subjects across multiple sites.
Scale: Hundreds to thousands of participants are included to evaluate the vaccine’s efficacy under natural disease conditions.
Outcome: If successful, these trials provide the data needed for regulatory authorities to consider granting a license for the vaccine’s market authorization for human use.
Phase IV - Post-Marketing Surveillance:
Objective: Post-marketing surveillance occurs after the vaccine is approved and available for use.
Focus: The aim is to detect any rare adverse effects that may not have been evident in earlier phases, as well as to assess the long-term efficacy and safety of the vaccine.
Monitoring: Continuous monitoring helps ensure that the vaccine remains safe and effective in a larger, more diverse population.
What is a polyvalent vaccine?
A polyvalent vaccine is a type of vaccine that provides protection against multiple strains or types of a particular pathogen or multiple related pathogens. The term “polyvalent” is derived from “poly,” meaning many, and “valent,” referring to the valency or the number of antigens a vaccine targets.
In the context of your question about the tetravalent rhesus-human reassortment rotavirus vaccine (RotaShield), “tetravalent” indicates that the vaccine is designed to protect against four different strains of rotavirus. Rotaviruses are a group of viruses that are a common cause of severe diarrhea, especially in infants and young children. The tetravalent rotavirus vaccine aims to induce an immune response that provides protection against multiple strains of rotavirus, offering a broader spectrum of coverage compared to monovalent or bivalent vaccines targeting fewer strains.
It’s important to note that the example you provided, RotaShield, faced challenges and was eventually withdrawn from the market due to an association with an increased risk of intussusception in children.
explain BioThrax
It seems like you’ve provided information about BioThrax, the only FDA-licensed human anthrax vaccine in the USA, along with details about anthrax and its potential consequences. BioThrax is manufactured by Emergent BioDefense Corp. Here are some additional points and clarifications:
Subunit Vaccines:
BioThrax is a subunit vaccine, meaning it is composed of specific components of the pathogen rather than the whole, inactivated pathogen itself.
In the case of BioThrax, the vaccine contains protective antigen, a key component of the anthrax bacterium (Bacillus anthracis). This approach allows for the stimulation of an immune response without the risk of causing the disease.
Bacillus anthracis Spores:
Bacillus anthracis, the bacterium that causes anthrax, can form highly resistant endospores. These endospores are the dormant, tough, and resilient form of the bacterium.
The spores can be used as a bioweapon due to their ability to persist in the environment and their potential to cause infection when inhaled or through contact with broken skin.
Anthrax Infection:
Anthrax infection can occur through inhalation of spores, ingestion, or contact with broken skin.
Inhalation of anthrax spores can lead to a severe form of the disease that affects the lungs and is often fatal if not treated promptly.
Clinical Manifestations:
Cutaneous anthrax, resulting from spore contact with the skin, can lead to painless, large, black skin lesions.
Inhaled anthrax can progress to severe respiratory symptoms and, if untreated, can lead to systemic effects such as septicemia, shock, and death.
BioThrax Vaccine:
BioThrax is administered subcutaneously (under the skin) and is used for pre-exposure vaccination to protect individuals at risk of exposure to anthrax, such as certain military personnel and laboratory workers.
It is also used in combination with appropriate antibiotic treatment for post-exposure prophylaxis.
explain the mechanism by which the anthrax exotoxin, consisting of Protective Antigen (PA), Edema Factor (EF), and Lethal Factor (LF), exerts its toxic effects upon entering host cells
The information you provided describes the mechanism by which the anthrax exotoxin, consisting of Protective Antigen (PA), Edema Factor (EF), and Lethal Factor (LF), exerts its toxic effects upon entering host cells. Let’s break down the key steps in this process:
PA (B Subunit) Binding:
Targets: PA, the B subunit of the exotoxin, binds to specific cell-surface receptors, including TEM8 (tumor endothelial marker 8) and CMG2 (capillary morphogenesis gene 2).
PA83 Cleavage:
Activation: PA83 undergoes cleavage by a membrane protease, leading to the formation of two fragments: PA20 and PA63.
Formation of Pre-Pore Complex:
Assembly: PA63 assembles into heptameric or octameric rings on the cell surface membrane, forming a pre-pore complex.
Binding of EF and LF:
Association: The pre-pore complex binds several copies of the A subunits, Edema Factor (EF), and Lethal Factor (LF).
Endocytosis:
Internalization: The entire complex, consisting of PA63 and associated EF and LF, is endocytosed into the host cell.
Low pH-Induced Changes:
pH Reduction: Inside the endosome, the pH decreases.
Conformational Change: The pre-pore complex undergoes a conformational change in response to the low pH, forming a cation channel.
EF and LF Entry into Cytosol:
Transport: The low pH-induced changes in the pre-pore complex enable the entry of EF and LF into the host cell cytosol through the cation channel.
EF (Edema Factor) Action:
Function: EF is a calcium (Ca2+)-calmodulin (CaM) dependent adenylate cyclase.
Effect: EF increases intracellular cyclic AMP (cAMP) levels, which can lead to a reduction in macrophage function.
LF (Lethal Factor) Action:
Function: LF is a zinc (Zn2+)-dependent endoprotease.
Effect: LF cleaves and inactivates mitogen-activated protein kinase kinases (MAPKKs), leading to disruption of cell signaling pathways, ultimately resulting in apoptosis (programmed cell death). This process kills macrophages and contributes to the pathogenic effects of anthrax.
explain the characteristics of attenuated vaccines, using the example of the Oral Poliovirus Vaccine (OPV), also known as the Sabin vaccine
Attenuated Vaccines:
Attenuated vaccines are live, weakened forms of the pathogen that are less virulent than the wild-type strain. They are capable of inducing an immune response without causing the disease.
Example: Oral Poliovirus Vaccine (OPV):
OPV is an attenuated vaccine used to protect against poliovirus infections.
Manufacture of OPV (Sabin Vaccine):
Passage Through Non-Human Cells: The vaccine virus is cultured by passage through non-human cells at subphysiological temperatures. This process leads to increased mutations in the viral genome.
Mutation in IRES: A key mutation occurs in the Internal Ribosome Entry Site (IRES) of the viral genome. IRES is a specific region that allows for the translation of viral mRNA without the typical 5’-cap structure.
Properties of Attenuated OPV:
Replication in Gut, Not Nervous System: The attenuated virus can replicate in the human gastrointestinal tract, inducing an immune response. Importantly, it is designed to be attenuated specifically for neurovirulence, meaning it should not cause infection in the nervous system.
Concerns with Attenuated Vaccines:
Rare Reversion to Virulence: While attenuated vaccines are generally safe, there is a rare risk that the vaccine strain can revert to a more virulent form. In the case of OPV, there have been instances where the attenuated poliovirus in the vaccine reverted to a form capable of causing paralysis.
Vaccine-Induced Paralysis:
Rare Events: Vaccine-induced paralysis is a rare event but underscores the importance of monitoring and surveillance.
OPV and Circulating Vaccine-Derived Polioviruses (cVDPVs): The rare instances of vaccine-induced paralysis are often associated with the circulation of vaccine-derived strains of poliovirus in under-vaccinated populations.
Global Polio Eradication Efforts:
Transition to Inactivated Poliovirus Vaccine (IPV): Due to the rare risk of vaccine-derived poliovirus cases, many countries have transitioned to using the Inactivated Poliovirus Vaccine (IPV) for routine immunization. IPV does not carry the same risk of vaccine-derived strains.
The use of attenuated vaccines, while highly effective, requires careful monitoring and public health measures to minimize the rare risks associated with reversion to virulence.
explain the Human Rotavirus (HRV) vaccine, which is developed by GlaxoSmithKline
HRV (Human Rotavirus) Vaccine:
Strain: The vaccine is based on an attenuated G1P strain of rotavirus.
Administration: It is administered orally.
Significance of Rotavirus:
Leading Cause of Diarrhea-related Illness: Rotavirus is recognized as a leading cause of diarrhea-related illness and death among infants.
Global Impact: The disease caused by rotavirus results in a significant global health burden, contributing to the death of more than 600,000 children under 5 years old each year.
Vaccine Efficacy:
Efficacy: The HRV vaccine has demonstrated 85% efficacy.
Statistical Significance: The efficacy is stated to be statistically significant (p < 0.001), indicating a high level of confidence in the vaccine’s ability to prevent rotavirus infection.
Intussusception Risk:
No Increased Risk: Unlike some earlier rotavirus vaccines, the information provided suggests that the HRV vaccine does not carry an increased risk of intussusception. Intussusception is a serious condition where one part of the intestine slides into another, potentially causing a blockage.
Overall Implications:
The development and use of an effective and safe rotavirus vaccine, such as the HRV vaccine, play a crucial role in preventing rotavirus infections and associated severe outcomes, including diarrhea-related illness and death in young children.
The absence of an increased risk of intussusception is a notable point, as this has been a concern associated with some previous rotavirus vaccines.
What is febrile respiratory syndrome?
“Febrile respiratory syndrome” is a general term referring to a set of symptoms characterized by fever and respiratory symptoms, such as cough, sore throat, or difficulty breathing. This syndrome can be caused by various infectious agents, including viruses and bacteria. In the context of the information you provided about the vaccine developed by the U.S. military, it seems that the vaccine was administered to recruits to prevent febrile respiratory syndrome.
It’s important to note that “febrile respiratory syndrome” is a broad and nonspecific term. The specific cause of febrile respiratory symptoms would depend on the infectious agent involved. Vaccines developed to prevent respiratory infections, especially in military populations, are designed to protect against specific pathogens that may cause respiratory illnesses.
explain the development of BioThrax and the specific characteristics of Bacillus anthracis, the bacterium responsible for anthrax
BioThrax Development:
Source: BioThrax is developed from culture filtrates of a toxin-producing but avirulent strain known as V770-NP1-R. This strain is derived from the U.S. weapon strain of Bacillus anthracis.
Avirulent Strain: The term “avirulent” indicates that this strain lacks the ability to cause disease, but it still produces certain toxins.
Bacillus anthracis Virulence Factors:
Plasmids: Bacillus anthracis carries plasmids, which are small, circular DNA molecules separate from the chromosomal DNA.
pXO1 Plasmid: Codes for the production of the anthrax exotoxin. This exotoxin is an ‘AB toxin,’ consisting of protective antigen (PA), edema factor (EF), and lethal factor (LF). The B subunits of the toxin deliver the active A subunits into the target cell.
pXO2 Plasmid: Codes for the production of a polypeptide capsule composed of poly-D-gamma-glutamate. This capsule provides protection by resisting phagocytosis (engulfing by immune cells) and hindering immune detection.
Exotoxin (AB Toxin):
Components: The exotoxin consists of three components - PA, EF, and LF. PA is the protective antigen that facilitates the entry of the other two components into the target cell.
Function: The exotoxin plays a crucial role in the virulence of Bacillus anthracis, contributing to the severity of the disease.
Capsule Formation:
pXO2-Encoded Capsule: The capsule formed by poly-D-gamma-glutamate is a protective structure that contributes to the bacterium’s ability to evade the immune system.
Avirulent Strain and pXO2 Absence:
Lack of Capsule Formation: The avirulent strain used for BioThrax lacks the pXO2 plasmid, which means it does not produce the protective capsule. This absence of the capsule likely contributes to the strain’s avirulence.
What do you conclude about the risk of cancer from Ad vaccine from these data?
To interpret the data presented, we can examine the odds ratios (OR) and their 95% confidence intervals (CI) for different types of cancer in relation to the Ad (adenovirus) vaccine. The odds ratio represents the odds of an event occurring in the exposed group (vaccinated) compared to the unexposed group (non-vaccinated). The 95% confidence interval provides a range within which we can be 95% confident that the true odds ratio lies.
Let’s break down the findings for each type of cancer:
Brain Tumors:
Odds Ratio (OR): 0.81
95% CI: 0.52-1.24
Interpretation: The odds ratio is less than 1, suggesting a lower odds of brain tumors in the vaccinated group compared to the unvaccinated group. The confidence interval includes 1, indicating that this result is not statistically significant.
Mesothelioma:
Odds Ratio (OR): 1.41
95% CI: 0.39-5.15
Interpretation: The odds ratio is greater than 1, suggesting a higher odds of mesothelioma in the vaccinated group, but the wide confidence interval indicates substantial uncertainty. This result is not statistically significant.
Non-Hodgkin’s Lymphoma:
Odds Ratio (OR): 0.97
95% CI: 0.65-1.44
Interpretation: The odds ratio is close to 1, suggesting a similar odds of non-Hodgkin’s lymphoma in both the vaccinated and unvaccinated groups. The confidence interval includes 1, indicating that this result is not statistically significant.
Conclusion:
The findings do not provide strong evidence of a significant association between Ad vaccine and an increased risk of brain tumors, mesothelioma, or non-Hodgkin’s lymphoma.
The confidence intervals for all three types of cancer include 1, indicating that the results are not statistically significant, and the observed associations may be due to chance.
explain viruses as vectors
The concept of using viruses as vectors for delivering antigens from other pathogens has been explored in vaccine development. These vaccines, known as viral vector vaccines, leverage the ability of certain viruses to efficiently enter cells and deliver genetic material. By using these viral vectors, scientists can introduce genes encoding antigens from other pathogens, stimulating an immune response against those specific antigens.
Some commonly used viral vectors in vaccine development include:
Vaccinia Virus:
Use: Vaccinia virus, which is part of the poxvirus family, has been extensively used as a viral vector in vaccine development.
Example: The smallpox vaccine, which is based on the vaccinia virus, was highly effective in eradicating smallpox.
Adenovirus:
Use: Adenoviruses, which can cause respiratory and gastrointestinal infections in humans, have been modified for use as viral vectors.
Example: Adenovirus vector vaccines have been developed for various diseases, including COVID-19. They are used to deliver genetic material that codes for specific antigens, prompting an immune response.
Vesicular Stomatitis Virus (VSV):
Use: VSV has been explored as a viral vector for vaccines.
Example: VSV-based vectors have been investigated for diseases such as Ebola virus and are being studied for other applications.
Herpes Simplex Virus (HSV):
Use: HSV has been considered as a potential vector for gene delivery, including vaccine development.
Example: Research is ongoing to explore the use of HSV vectors for various applications, including cancer immunotherapy.
Viral vector vaccines offer several advantages, including their ability to induce strong immune responses, especially cellular immunity. However, there are challenges and considerations, such as pre-existing immunity to the viral vector in the population and potential safety concerns.
In the context of your question, viruses carrying antigens from different pathogens can indeed be used to develop vaccines. This approach allows for the development of vaccines against a wide range of diseases beyond those caused by the specific viruses used as vectors.
explain the aspects of a viral vector used in gene therapy, particularly the Ad5 (adenovirus serotype 5) vector
The information you provided outlines aspects of a viral vector used in gene therapy, particularly the Ad5 (adenovirus serotype 5) vector. Let’s break down the key points:
Viral DNA Entering Nucleus:
The adenovirus vector is designed to enter the host cell’s nucleus, where it can deliver its genetic material.
Integration into Host DNA:
Adenoviruses very rarely integrate their DNA into the host genome. Unlike retroviruses, adenoviruses lack the machinery necessary for stable integration.
Use of Retroviral Integration Machinery:
In gene therapy applications, adenoviral vectors may combine with retroviral integration machinery to facilitate the expression of the delivered genes.
Gene Therapy Vector:
Adenoviral vectors are commonly used in gene therapy to introduce therapeutic genes into target cells.
Delivery of Antigens for Immune Response:
In the context of vaccines, adenoviral vectors can be designed to deliver antigens to target cells. These antigens are then presented to immune cells through major histocompatibility complex (MHC) molecules.
Induction of Cytotoxic T-Cell Response:
Adenoviral vectors have the capability to generate a strong cytotoxic T-cell response, which is crucial for effective immune responses against intracellular pathogens or cancer cells.
Ad5 Clinical Trials:
Clinical trials involving the Ad5 vector have demonstrated safety and effectiveness, supporting its use in various applications, including gene therapy and vaccine development.
No Adjuvant Needed:
An adjuvant is a substance added to vaccines to enhance the body’s immune response. The note mentions that Ad5 vectors do not require an adjuvant, suggesting their intrinsic ability to elicit a robust immune response.
Challenges:
Pre-existing Immunity: Adenoviruses, including Ad5, are common viruses, and many individuals may have pre-existing immunity due to prior exposure. Pre-existing immunity can decrease the efficiency of the vector by neutralizing the virus before it can deliver its payload. This is a notable challenge in the use of adenoviral vectors.
explain the use of adenovirus (Ad) as a vaccine vector, particularly in the context of replacing specific encoding regions with cargo genes for vaccine development
Adenovirus (Ad) as a Vaccine Vector:
Cargo Gene Replacement:
The vaccine vector involves replacing specific adenovirus encoding regions, such as E1A and E1B, with cargo genes. This modification allows the adenovirus to deliver the desired antigens or genes for vaccination.
E1A and E1B Encoding Regions:
E1A: This is the first adenovirus protein produced following cell entry. It plays a role in activating other early gene promoters.
E1B: An early gene that produces two proteins. One of its functions is to decrease the activity of the p53 protein, which is involved in regulating cell cycle and apoptosis. This reduction in p53 activity may contribute to the inhibition of apoptosis, which is a mechanism involved in host cell → tumor cell transition.
Examples of Adenovirus Vaccine Vectors:
Example 1 - AdRG1:
Nature: Replication competent, recombinant Ad5.
Cargo Gene: Rabies glycoprotein (RG).
Administration: Given orally.
Results: Induces immunity to rabies in rodent, canine, and skunk models.
Example 2 - Ad85A + Mycobacterium tuberculosis Antigen 85A:
Nature: Adenovirus vector expressing Mycobacterium tuberculosis antigen 85A.
Administration: Given intranasally.
Results: Induces strong CD8 T cell immunity in the lungs of mice.
These examples demonstrate the versatility of adenoviral vectors in delivering various cargo genes to induce specific immune responses.
Potential Applications:
Adenoviral vectors are versatile tools in vaccine development, capable of inducing both antibody and cellular immune responses.
The ability to replace adenovirus encoding regions with specific cargo genes allows for the development of vaccines targeting a variety of pathogens, including viruses and bacteria.
Considerations:
The choice of cargo genes and the specific design of the adenoviral vector play a crucial role in determining the effectiveness of the vaccine.
Intranasal administration, as in the second example, is a route that can induce strong mucosal and lung-specific immune responses.
Rhabdovirus (Lyssavirus)
What functions do you think the G antigen has?
The G antigen in rhabdoviruses, including lyssaviruses such as the rabies virus, plays a crucial role in the virus’s life cycle and pathogenesis. The G antigen refers to the glycoprotein on the surface of the virus particle. Here are some key functions associated with the G antigen in rhabdoviruses:
Virus Attachment and Entry:
The G glycoprotein is responsible for mediating the attachment of the virus to host cell receptors. It recognizes and binds to specific receptors on the surface of host cells, facilitating virus entry.
Cell Fusion:
In some rhabdoviruses, including certain strains of the rabies virus, the G glycoprotein has been implicated in the process of cell fusion. This involves the merging of the viral envelope with the host cell membrane, allowing the virus to enter the cell.
Induction of Immune Responses:
The G antigen is a major target for the host’s immune system. Antibodies generated against the G glycoprotein can neutralize the virus, preventing its entry into host cells and aiding in the clearance of the infection.
Virulence Determinant:
The G glycoprotein is often considered a virulence determinant, meaning that variations or mutations in the G protein can influence the pathogenicity of the virus. It can affect the ability of the virus to replicate and spread within the host.
Vaccine Target:
The G glycoprotein is a common target for vaccine development against rhabdoviruses. Vaccines designed to induce an immune response against the G antigen can confer protection by preventing virus attachment and entry into host cells.
Host Tropism:
The G glycoprotein may contribute to the determination of host cell tropism, influencing which types of cells the virus can infect.
explain the common excipients found in vaccines
In addition to the active components (antigens or inactivated pathogens) that stimulate an immune response, vaccines may contain various excipients, which are inactive substances used to improve the stability, effectiveness, and safety of the vaccine. These excipients serve various purposes and can include substances like stabilizers, preservatives, adjuvants, and diluents. Here are some common excipients found in vaccines:
Stabilizers:
Purpose: Help maintain the stability and effectiveness of the vaccine during storage and transportation.
Examples: Dextrose, sucrose, sorbitol.
Preservatives:
Purpose: Prevent microbial contamination and increase the shelf life of the vaccine.
Examples: Thiomersal (ethylmercury), formaldehyde.
Note: Thiomersal, despite containing mercury, is used in tiny amounts and has been shown to be safe in vaccines. It is primarily used in multidose vials to prevent bacterial and fungal contamination.
Adjuvants:
Purpose: Enhance the body’s immune response to the vaccine.
Examples: Aluminum salts (e.g., aluminum hydroxide, aluminum phosphate).
Diluents:
Purpose: Used to reconstitute vaccines that come in a freeze-dried (lyophilized) form before administration.
Examples: Sterile water for injection.
Surfactants:
Purpose: Improve the stability and dispersion of the vaccine components.
Examples: Polysorbate 80.
Buffering Agents:
Purpose: Maintain the pH of the vaccine to ensure stability.
Examples: Phosphates, citrates.
Antibiotics:
Purpose: Used as preservatives to prevent bacterial contamination.
Examples: Neomycin, streptomycin.
Emulsifiers:
Purpose: Help disperse and stabilize the oil-water phases in certain vaccines.
Examples: Sorbitan trioleate.
It’s important to note that the use of specific excipients can vary between different vaccines, and vaccine formulations may differ based on factors like the type of vaccine, its intended use, and regulatory guidelines.
Concerns regarding vaccine components, such as thiomersal, have led to modifications in vaccine formulations. Thiomersal, for example, is now generally reduced or eliminated from routine childhood vaccines in the United States and Europe. Additionally, single-dose vials and pre-filled syringes often do not contain thiomersal.
